Winner 2008 – Klaus-Peter Lesch

The ECNP Neuropsychopharmacology Award has been established to recognise distinguished research in neuropsychopharmacology and closely related disciplines. This year’s prize recognises contributions in clinical research, and the awardee is Klaus-Peter Lesch, Professor of Psychiatry and Psychotherapy at the University of Würzburg, Germany. The award jury has based its decision on Prof. Lesch’s pioneering and innovative research on a polymorphism on the promoter of the serotonin transporter gene and his subsequent discoveries of the importance of this finding for personality disorders and a number of psychiatric disorders.
Klaus-Peter Lesch received his undergraduate training at the Medical school during 1977-1981 and his postgraduate education at the University of Würzburg. He received a fellowship at the National Institute of Health (NIH), Bethesda, USA 1990-1992 and his certificate in psychotherapy and psychiatry in 1993. In 2000, he was appointed Professor at the Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg. Klaus-Peter Lesch has published more than 260 original papers, most of them in high ranking scientific journals. He is one of the most cited researchers in the field according to the Institute for Scientific Information (ISI) and he has received several international prestigious awards and distinctions.

The research of Klaus-Peter Lesch has been focused on basic and clinical neuropsycho-pharmacology with internationally recognised contributions in neuropsychopharmacology and pharmacogenetics. A major theme in his studies is the role of the brain serotonin (5-HT) system in disorders of attention, emotion regulation and cognition. The work has led to important discoveries on the neurobiology of the 5-HT1A-receptor subtype (5-HT1A), 5-HT transporter (5-HTT) and monoamine oxidase A (MAOA) in anxiety, aggression and depression. By using techniques from molecular genetics to clinical psychiatry Klaus-Peter Lesch has elucidated the role of altered intraneuronal signalling as well as interneuronal interactions in various phenotypes. These findings have increased our knowledge on the multiple mechanisms underlying the pathophysiology of neuropsychiatric disorders and have given indications of the final common pathways which could be targeted by drug treatments. An important aspect of this research is based on the development of relevant preclinical models in mice. Klaus-Peter Lesch and his group have been the first to generate mutant mice deficient in 5-HTT and tryptophan hydroxylase 2 (TPH2).

Together with Dr Dennis Murphy and his co-workers from the NIH, Klaus-Peter Lesch started to examine the role of 5-HTT in emotional regulation in the early 1990’s.
5-HTT fine-tunes 5-HT transmission at the synapse since it removes the transmitter from the synaptic cleft. 5-HTT is known to have a critical role in the mechanisms of action of antidepressant drugs since most antidepressant drugs and in particular serotonin reuptake blockers (SSRI’s) act on this receptor site. The collaboration with Dennis Murphy and his group led to pioneering discoveries on the role of gene polymorphisms associated with personality traits, response to psychotropic drugs and various psychiatric disorders. A particularly important finding (published in Science,1996) relates to the discovery of an association between anxiety-related traits with a polymorphism in the promoter of the gene which encodes 5-HTT. In several fundamental papers Klaus-Peter Lesch and his group demonstrated the functional consequences of the polymorphism at the 5-HTT promoter which results inter alia in variations in 5-HT neurotransmission. Thus, the short (S) promoter variant of the gene resulted in a different expression of 5-HTT compared to the long (L) variant. Subsequent studies have demonstrated that polymorphism of the 5-HTT gene promoter is associated with several personality traits including anxiety and susceptibility to depression. In recent studies it was demonstrated that the similar S and L-related polymorphisms not only exist in man but also in non-human primates which allowed studies to directly assess the importance of gene-environment interactions under strictly controlled social conditions. With this knowledge, important gene-environment interactions have been demonstrated both in humans, primates and rodents. Importantly, Klaus-Peter Lesch and his group demonstrated that stress during a critical period in development is more detrimental for emotion regulation, social cognition and stress reactivity in monkeys carrying the S genotype.

The above described research paradigm has recently been extended to complex human phenotypes including e.g. social interaction and emotion regulation showing a broad role of the 5-HTT-gene in the modulation of complex human behaviour. Klaus-Peter Lesch is currently investigating the neuronal and molecular pathways modulated by 5-HTT genetic polymorphisms and how they relate to psychopathology. This research, based on integration of behavioural genetics and cognitive neuroscience, will open up a deeper understanding of the complexity in human behaviour and how this relates to gene-environment interactions.

In summary, because of his pioneering and creative scientific achievements, Klaus-Peter Lesch is one of the pre-eminent researchers in the field of neuropsychopharmacology.